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The manuscript by Pardossi-Piquard et al. (Neuron, 2005) provides an impressive array of experiments suggesting that the γ-secretase-derived intracellular domains (ICDs) of APP and APLPs serve to regulate the transcription of neprilysin (NEP). This paper is of high interest, first, because NEP is a key regulator of β-amyloid levels and amyloid pathology in vivo (Iwata et al., 2000; Iwata et al., 2001; Leissring et al., 2003) and second, because it adds strength to the evidence that APP may be a signaling molecule acting to regulate the transcription of genes through a mechanism that may or may not be analogous to Notch signaling (e.g., Cao and Sudhof, 2001; Leissring et al., 2002; Cao and Sudhof, 2004; Hass and Yankner; SfN abstract 146.4, 2004; among others).

Beyond these important aspects, however, it is interesting to consider the results of Pardossi-Piquard and colleagues in relation to the finding that APP and APLP ICDs are rapidly and efficiently degraded by insulin-degrading enzyme (IDE) both in vitro (Edbauer et al., 2002; Walsh et al., 2003) and in vivo (Farris et al., 2003; Miller et al., 2003). Of course, IDE has additional numerous substrates besides the ICDs of APP and APLPs, so the following comments should be interpreted in this context. Nonetheless, several points should be made with regard to the interplay between IDE, ICD levels, and NEP.

First, NEP levels were found to be unchanged in IDE knockout mice (Farris et al., 2003), which themselves had significantly elevated levels of non-phosphorylated ICDs (Farris et al., 2003; Miller et al., 2003). It is notable that phosphorylated forms of APP ICD were found to be unchanged in IDE knockout mice (Farris et al., 2003); however, this finding does not appear to explain the apparent conflict with the work of Pardossi-Piquard and colleagues, since these investigators found significant upregulation of NEP upon overexpression of cDNAs encoding the ICDs of APP or APLPs, which presumably would not be phosphorylated to any significant extent. Perhaps the discrepancy relates to the absolute magnitude of the changes in ICD levels or to other factors that differ in the in vitro versus the in vivo paradigms.

Second, other in vivo work from our group (Leissring et al., 2003) lends some support to the notion that IDE can influence NEP expression levels, but it is not clear that this involves the mechanism proposed by Pardossi-Piquard and colleagues. In this work, transgenic overexpression of IDE to modest levels (~100 percent increase) in neurons did, in fact, lead to decreases in endogenous NEP levels and activity levels. However, it should be pointed out that we did not directly determine APP ICD levels in the IDE transgenic mice, and the decrease in NEP levels, while discernable in some animals, was variable and did not achieve statistical significance. Interestingly, however, in that same study, transgenic overexpression of NEP (by ~700 percent) led to significant downregulation of IDE. Taken together, these findings seem to suggest that some "extracellular" substrate common to the two proteases (perhaps β-amyloid itself; see Mohajeri et al., 2002) was responsible for their cross-regulation, since NEP, a type II membrane-bound protease, does not act on intracellular substrates. In light of the work of Pardossi-Piquard and colleagues, this topic deserves further careful study.

Third, if ICD levels can indeed upregulate NEP levels, then it raises the curious possibility that inhibition of "intracellular" IDE—by increasing ICD levels—might represent a therapeutic strategy for combating Alzheimer disease. Inhibition of all pools of IDE non-selectively would, of course, not be viable, given the fact that IDE knockout mice show elevated, rather than reduced, β-amyloid levels (Farris et al., 2003; Miller et al., 2003). Moreover, IDE appears to be the major protease involved in the degradation of extracellular β-amyloid in cultured primary neurons (see Fig. 1B in Farris et al., 2003), suggesting that extracellular pools of IDE are more important to the regulation of β-amyloid than are intracellular pools (albeit the cellular locus of β-amyloid degradation by IDE is presently unclear).

In summary, IDE knockout mice show clear elevations in ICD levels, yet do not show significant elevation in NEP levels, a result that tends to cast some doubt on the idea that increasing ICD levels per se will lead to upregulation of NEP in the brain in the intact animal. On the other hand, transgenic overexpression of IDE in neurons did lead to a decrease in NEP levels in some animals, though this change was variable and not significant across all animals examined. These results can perhaps be reconciled if we assume that levels of Tip60 and Fe65—essential cofactors for the ICD-mediated regulation of downstream genes (Cao and Sudhof, 2001)—are limiting in the normal mouse brain, making reductions—but not increases—in NEP levels possible through this mechanism. Even if ICD regulation turns out to be a tough target for combating Alzheimer disease, the tantalizing findings of Pardossi-Piquard and colleagues recommend closer scrutiny of the physiologic consequences of ICD regulation by IDE.

The results reported by Raphaelle Pardossi-Piquard and colleagues are most interesting and also provocative. The implication is that the amyloid peptides (any or all) exert a physiologic function (which I have not seen demonstrated), and that this function is indirectly controlled or terminated by its "co-metabolite" AICD via induction of increased NEP expression.

Questions that arise are plenty: Does that mean control of a "constant stream" of Aβ or is its production modulated or even triggered? By what signals? In which brain regions? And how indirect is control by AICD/NEP, that is, what is the timeframe or delay between generation of Aβ and induction of NEP?

On the other hand, if production of ALID1 and ALID2, evidently without co-production of Aβ from APLP1 or APLP2, also induce NEP, the regulatory connection or relation among Aβ/AICD/NEP is not evident or at least much more indirect.

A final note concerns a recent report that NEP is selective for Aβ42 degradation in vivo (Saito et al., 2005). Does that imply that only Aβ42 is physiologically functional, or rather that different control mechanisms control the different Aβ peptides?

As stated above, the study is provocative in generating these and several other questions.